Pathogens commonly exploit host functions with molecular mimicry. Virus-encoded mimics often arise through horizontal transfer of host genes into pathogen genomes. After acquisition, these genes diverge under strong natural selection and gain new functions disrupting or coopting host processes. Classically studied examples of mimics include viral oncogenes like v-Src and v-Ras that were acquired from host genomes. Additional cases of mimicry are increasingly recognized for playing pivotal roles in the success of a diverse array of human pathogens. Despite extensive observations of mimicry, the origins and evolutionary mechanisms underlying adaptation of such pathogen genes to mimic host forms are not well understood. We have developed innovative experimental systems using vaccinia virus, the model poxvirus, to investigate the evolution of mimicry. Poxviruses deploy an abundance of mimics to defeat host defenses and can cause devastating diseases. Smallpox, for instance, likely caused more human fatalities than any other pathogen before eradication and related viruses seem poised to emerge as epidemics. To study the evolution of molecular mimicry, we are reconstructing the origins of mimics with a series of experiments selecting for horizontal gene transfer of host genes into vaccinia genomes through experimental evolution. This system provides a versatile means of capturing horizontal gene transfer events to investigate mechanisms underlying pathogen adaptation. Once pathogens acquire host factors they often diverge in ways that increase pathogen fitness, but little is known about how this process unfolds. In another major set of experiments, we have developed a means for reconstructing the adaptive process in which newly acquired host genes diverge to become mimics. Finally, we are investigating the ongoing evolution of mimics as viruses adapt to host defenses. These studies have already revealed newly described mechanisms of virus adaptation. Evolutionary-guided approaches for studying mimicry hold great promise for enriching anti-viral interventions and bolstering traditional strategies of vaccination. Our multi-faceted approach combining virology, evolutionary genetics, and molecular biology will provide insight into fundamental mechanisms of pathogen adaptation and new prospects for leveraging mechanisms of mimicry to promote human health.